The selective tachykinin NK 1 receptor antagonist, 2-( R )-(1-( R )-3,5-Bis(trifluoromethyl)phenylethoxy)-3-( S )-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine (MK-869), has been recently described as a novel therapeutic approach for anxiety/depression. A frequently used model to establish the central nervous system (CNS) activity of tachykinin NK 1 receptor antagonists is the inhibition of NK 1 agonist-induced foot tapping in gerbils. In the present study, we demonstrate that foot tapping can also be induced in most, but not all, gerbils by footshock and associated cues. MK-869 (0.3–3 mg/kg, i.p.) dose-dependently blocked this foot tapping response. This effect was further shown to be due to selective NK 1 receptor blockade, since (2 S ,3 S )- cis -3(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994; 3 mg/kg, i.p.) inhibited foot tapping, whereas its less active enantiomer (2 R ,3 R )- cis -3(2-methoxybenzylamino)-2-phenylpiperidine (CP-100,263; 3 mg/kg, i.p.) had no effect. Diazepam (1–10 mg/kg, i.p.) also inhibited foot tapping, whereas fluoxetine (10–30 mg/kg, i.p.) markedly increased this behaviour. The present data support the view that foot tapping in the gerbil is a behavioural response to an aversive stimulus, and is robustly inhibited by two NK 1 receptor antagonists. The data support a role for tachykinin NK 1 receptor antagonists as novel anxiolytic/antidepressants.
European Journal of Pharmacology – Elsevier
Published: Feb 2, 2001
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